Discovery of N-Aryl-N′-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation,Journal of Medicinal Chemistry

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Discovery of N-Aryl-N′-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-11 , DOI: 10.1021/acs.jmedchem.4c01597
Long Huu Nguyen ₁ , Ye Eun Cho ₁ , Soyeong Kim _{1,

2} , Yeonsoo Kim ₁ , Jinsook Kwak ₁ , Jung-Soo Suh ₃ , Jinyoung Lee ₁ , Kyuwon Son ₁ , Minseong Kim ₁ , Eun Seo Jang ₁ , Naghyun Song ₁ , BuChul Choi ₁ , Jiah Kim ₁ , Yealin Tak ₁ , Taeyeon Hwang ₄ , Jeyun Jo ₁ , Eun-Woo Lee ₅ , Sang-Bum Kim ₂ , Sanghyun Kim ₆ , Oh-Bin Kwon ₂ , Sangok Kim ₄ , Seoung Rak Lee _{1,

7} , Haeseung Lee _{1,

7} , Tae-Jin Kim ₃ , Seonghwan Hwang _{1,

7} , Hwayoung Yun _{1,

7}

Affiliation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and other lipid metabolism-related diseases.

中文翻译：

基于 N-Aryl-N′-[4-（芳氧基）环己基]平方酰胺的 LXR/SREBP-1c 信号通路抑制剂改善脂肪性肝病的发现：探索 SIRT6 激活的作用

代谢功能障碍相关脂肪性肝病（MASLD）主要归因于肝脂肪生成的异常上调，尤其是由肝细胞中肝脏 X 受体/甾醇调节元件结合蛋白-1c （LXR/SREBP-1c）通路的过度激活引起的。在这项研究中，我们报告了通过生物等位置换合理设计和合成一系列新型方形酰胺，使用基于细胞的双重测定评估了其对 LXR/SREBP-1c 通路的抑制活性。发现化合物 31 显著下调 LXR 、 SREBP-1c 及其与脂肪生成相关的靶基因。进一步研究显示，化合物 31 可能通过激活上游调节因子 sirtuin 6 （SIRT6）间接抑制 LXR/SREBP-1c 通路。令人鼓舞的是，化合物 31 显着减轻了 HepG2 细胞和高脂肪饮食喂养小鼠肝脏中的脂质积累。这些发现表明，化合物 31 有望成为 MASLD 和其他脂质代谢相关疾病的治疗方法的候选者。

更新日期：2024-09-11

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